Cardiovascular Diseases
Hypertension accounts for 9.4 million cardiovascular (CV) deaths annually worldwide and is affecting more than two-thirds of people aged 65 years, an age group that is growing globally. The treatment of hypertension has been shown to reduce the risk of morbidity and mortality associated with elevated blood pressure (BP) including stroke, ischaemic heart disease, heart failure, chronic kidney disease and possibly cognitive decline. Despite the availability of multiple drug classes with different mechanisms of action, hypertension, especially systolic blood pressure (SBP), remains inadequately controlled.
The SBP usually increases from childhood throughout the life, while diastolic BP (DBP) remains relatively constant or decreases beyond 50 to 60 years of age. The changing patterns of BP throughout the life reflect different pathologies. In the young, hypertension is predominantly due to an increased DBP and mean arterial pressure (MAP), as a result of a relative increase in cardiac output and/or increased peripheral vascular resistance. On the other hand, advancing age, beyond mid-life, is associated with an increased stiffness of large elastic arteries, especially the aorta.
Arterial stiffening adversely affects the characteristic impedance of the aorta, requiring more cardiac work and raising SBP as more stroke volume is delivered during systole owing to the increased pulse wave velocity (PWV). DBP also decreases due to less elastic recoil leading to reduced flow, thus increasing pulse pressure (PP) independent of any changes in MAP. PWV been shown to be an independent predictor of CV outcomes, including mortality, myocardial infarction (MI), stroke, atrial fibrillation, cognitive decline and renal dysfunction, and more specifically aortic PWV (aPWV), a robust measure of aortic arterial stiffness, has been shown to predict the adverse CV outcomes.
Another consequence of arterial ageing and stiffening is that the amplification of SBP and PP from the aortic root to the peripheral arteries diminishes. In a healthy arterial system, central aortic systolic pressure (CASP) and PP are amplified as they move towards the periphery, such that the measured brachial systolic pressure is typically 10 to 12 mm Hg higher than the corresponding aortic root pressure. With ageing, this amplification is reduced and the measured brachial SBP and PP become closer to the corresponding aortic root pressures. Some studies have suggested that central pressures may have a closer correlation than peripheral BP with end organ damage and CV risk, such as extent of coronary atherosclerosis, carotid intima-media thickness, left ventricular (LV) hypertrophy, and left ventricular (LV) diastolic function.
These observations raise the intriguing question as to whether treatments used to lower blood pressure could differentially affect aortic relative to brachial pressures and also arterial stiffness per se. It has been demonstrated that BP-lowering drugs can have marked differential effects on central aortic pressure (CAP) and brachial BP. These effects mimic a functional anti-ageing effect in terms of their impact on wave-form morphology, and greater reduction in central pressures relative to brachial pressures. Intriguingly, the beta-blockers, a drug class which was least effective at lowering aortic pressure also appeared to be the least effective class at reducing the risk of stroke in elderly patients. This supports the concept that the more effective lowering of aortic relative to brachial pressure may be clinically important.
Despite the findings cited above, controlling SBP remains the most important unmet need in the clinical management of hypertension. The rise in SBP and PP with ageing appears to be strongly related to arterial stiffening and increased impedance to flow through a stiff aorta. This suggests that the treatments targeting aortic stiffening and reducing characteristic impedance would be effective particularly at reducing systolic pressure. Early proof of this concept came from the studies with omapatrilat, a vasopeptidase inhibitor that simultaneously inhibits neprilysin and angiotensin-converting enzyme (ACE). Neprilysin inhibition enhances natriuretic peptide (NP) levels by blocking their degradation. NP has vasodilating actions, which could reduce aortic stiffness, improve characteristic impedance and thereby reduce SBP and PP. Studies with omapatrilat show greater improvements in aortic characteristic impedance compared with enalapril, beyond the effects of BP-lowering after 12 weeks of therapy. This benefit on aortic function was also associated with impressive data on SBP and PP lowering in patients with hypertension.
Although omapatrilat was withdrawn due to safety concerns, a proof of concept was established for concomitant inhibition of neprilysin and renin-angiotensin-aldosterone system (RAAS) with the potential to be an attractive treatment strategy to improve aortic haemodynamics. Increased NP levels also promote natriuresis and reduce sympathetic tone, together with antiproliferative and antihypertrophic effects, and inhibition of aldosterone secretion. Alongside, suppression of RAAS would be complementary to neprilysin inhibition, which attenuates vasoconstriction, reduces sodium and water retention and also inhibits the development of CV hypertrophy and adverse re-modelling.
Thus, the big challenge in hypertension treatment is to reduce the SBP, and the available evidence suggests that this could be achieved by improving the haemodynamic performance of the ageing aorta.
Sacubitril and Valsartan (LCZ696)
LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) being developed for the treatment of cardiovascular diseases such as hypertension and/or heart failure. Ingestion of LCZ696 results in systemic exposure to sacubitril (AHU377; (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester, also named N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester), a neprilysin (neutral endopeptidase 24.11, NEP) inhibitor (NEPi) prodrug which is converted to the active form LBQ657 (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionyl amino)-2-methyl-pentanoic acid), and valsartan providing inhibition of the angiotensin II type 1 (AT1) receptor, in a 1:1 molar ratio.
It has been shown that LCZ696 at 100, 200 and 400 mg once daily, in patients with mild-to-moderate essential hypertension, resulted in greater BP reductions than corresponding doses of valsartan alone (160 and 320 mg) and was well tolerated [Ruilope L M, Dukat A, Bohm M, et al. Lancet 2010; 375: 1255-66]. LCZ696 compared with valsartan was effective especially at reducing brachial SBP and PP. Furthermore, in patients with heart failure with preserved ejection fraction, LCZ696 has shown to reduce N-terminal-pro B-type natriuretic peptide (NT-proBNP), a biomarker of left ventricular (LV) wall stress, to a greater extent than valsartan alone at 12 weeks and was well tolerated [Solomon S D, Zile M, Pieske B, et al. Lancet 2012; 380: 1387-95].
The compounds and pharmaceutical compositions disclosed herein include combinations of sacubitril and valsartan which compounds or pharmaceutical compositions thereof have been previously disclosed in WO 2003/059345, WO 2007/056546, WO 2009/061713, and WO 2014/029848, which are herein incorporated by reference.
Need
Overall there remains a great need to improve the haemodynamic performance of the ageing aorta and to improve, i.e. to reduce, arterial stiffness and pulse wave velocity (PWV), and thereby reducing the risk of cardiovascular events and to improve CV outcomes, reducing the risk of cognitive decline and provide a cognitive benefit, respectively, and/or reducing the risk of a cerebrovascular event.